As a result of frequent abuse of drugs by smoking or inhalation, a major of goal of this proposal is to study the pharmacological and toxicological effects of drugs of abuse by the inhalation route. A common practice for PCP abuse is smoking PCP-laced cigarettes. It is well-documented that PCP is readily degraded (about 50%) during the smoking process to several products. A specific aim of this grant is to examine PCP analogs that are abused to determine whether they are degraded to a similar extent and whether potentially dangerous pyrolytic products are formed. Cocaine is another drug that is abused primarily by the inhalation route. Although cocaine is smoked occasionally, it has become increasingly popular to "free base" cocaine, the process of inhaling the volatilized free based. Two particularly alarming aspects of "free basing" is that it increases both the addictive potential and the toxicity of cocaine. A goal of this research is to elucidate the mechanisms that are responsible for the changes in the pharmacological properties of cocaine following inhalation. A specific aim of this proposal is to quantitate cocaine and its pyrolysis products that are delivered in the vapor during a typical "free basing" session. Additionally, rats will be exposed to cocaine vapor so that the concentrations of cocaine and its pyrolysis products can be determined in plasma, brain, heart and lung. The time course of cocaine and pyrolysis products is these tissues can then be correlated with the effects of "free basing" on heart rate and blood pressure. There are also indications that PCP and cocaine have been co-abused. Upon completion of the cocaine inhalation studies, the consequences of co-administration of PCP and cocaine by inhalation can be assessed in terms of enhanced cardiovascular toxicity. If co-administration results in unexpected pharmacological effects, then biodisposition of PCP and cocaine will be studied following inhalation of the drug combination. The last objective is to continue our investigation of PCP site of action in the brain. While several different approaches are currently being employed to identify sites and mechanism(s) of PCP action in the central nervous system, our observation that PCP is relatively inactive following intraventricular (i.v.t.) administration in rats provides an exciting lead that warrants further investigation. Autoradiographic studies will be carried out to determine whether differences in the localization of PCP after i.v.t. and i.p. administration can explained the differences in potency by these two routes. The research proposed in this application will enables us to better understand the toxic manifestations of drugs or drug combinations when they are abused either by smoking or inhalation. An explanation for the toxicity of drugs of abuse by different routes of administration will enable rational therapies for medical emergencies to be developed as well as serving to educate the public of the dangers of drug abuse.